Di-tert-butyl Chloromethyl Phosphate

Di-tert-butyl Chloromethyl Phosphate has become one of the most common reagents to prepare phosphon-oxymethyl pro-drugs, generally by direct alkylation of hydroxyl or amino groups. Its synthesis was first reported in 1999 via a reaction of di-tert-butyl tetramethylammonium phosphate with chloroiodomethane. This approach required the use of the corresponding tetramethylammonium phosphate and a vast excess (>11 equiv) of chloroiodomethane to minimize the formation of tetra-tert-butyl methylene bisphosphate[1].

Used as an intermediate for laboratory research.

The prodrug was obtained through an alkylation of Albendazole employing Di-tert-butyl Chloromethyl Phosphate in DMF^[2].

Di-tert-butyl (chloromethyl) phosphate, a key compound in the formation of many phosphon-oxymethyl pro-drugs,  is prepared by reacting chloromethyl chlorosulfate (CMCS) with di-tert-butyl potassium phosphate (DTBPP) .

[1] Bin Zheng*. “Development of Efficient Processes for the Preparation of Di-tert-butyl Potassium Phosphate and Di-tert-butyl (Chloromethyl) Phosphate.” Organic Process Research & Development 18 5 (2014): 636–642.
[2] Becerril-Vega, J., Hernández-Campos, A., González-Hernández, I., Flores-Ramos, M., Castillo, R., Leyva-Gómez, G., Mayet-Cruz, L., & Jung-Cook, H. (2023). Development and Pharmacokinetic Evaluation of Two Parenteral Formulations of Albendazole Using Prodrug and Cosolvent Approaches. AAPS PharmSciTech, 24 6. https://doi.org/10.1208/s12249-023-02613-9